With diagnoses at 1 in 68 live births in the United States, autism spectrum disorders (ASD) have been considered one of the most increasing child neuropsychiatric diseases. ASD is a neurodevelopmental disability characterized by social interaction deficits and repetitive or stereotyped behaviors. Twin studies and linkage analysis confirm that genetic abnormalities and environmental susceptibilities contribute to ASD. Human epidemiological studies support that maternal exposure to environmental risks like prenatal infection significantly increases the risk for ASD in offspring. Abnormal maternal immune activation (MIA) during early pregnancy results in deleterious outcomes in the central nervous system (CNS) of the developing fetus. As a critical maternal-fetal interface, the placenta also plays a key role in immune surveillance as well as fetal growth, and placental injury is strongly associated with risks for neurodevelopmental disease. We have identified a placental vulnerability to lipopolysaccharide (LPS, a compound that mimics bacterial infections) that is modulated by GABA receptor type A (GABAAR). Intriguingly, various GABAAR subtypes are expressed not only in CNS but also in immune cells and other tissues, where GABA signaling is found to modulate immune response. The most common GABAAR anomaly found in ASD cases is a maternally inherited copy number variation (CNV) at 15q11-13 which is implicated in ASD, Angelman syndrome, Prader Willi syndrome. My studies focus on novel ASD-risk mechanisms involving gene-environment interaction between one of the GABAARs, GABRB3, and MIA in an ASD mouse model. I hypothesize that a maternally inherited partial loss of GABRB3 and MIA could exacerbate fetal pathological brain phenotypes. I will determine if GABRB3 and MIA generate synergistic adverse effects on neural progenitor cell (NPC) functions in early development. Previously, we demonstrated that prenatal LPS challenge causes cortical patterning alterations in offspring with a pronounced effect on the abundance of Satb2-expressing upper layer callosal neurons and neuronal layer formation during early neocortical development. Preliminary data suggest that partial loss of Gabrb3 function greatly increases placental damage following LPS exposure. A short-term goal is to determine if GABAAR function in mother or maternal immune cells underlies this effect. In the long-term, I will assess whether GABAARs are valid drug targets in a mouse model of ASD. Confirmation that alterations in maternal GABAARs increase risk of ASD phenotypes may also lead to novel diagnostics that can identify mothers at risk during pregnancy. From this proposed study, I expect to find the key candidate molecules working downstream of GABRB3-mediated genetic predisposition combined with MIA. Importantly, administration of antagonists or neutralizing antibodies against these key mediator molecules may restore normal function of the GABA-MIA axis, which may potentially provide critical insight into therapeutic strategies to reduce risk of ASD.